Targeting NF-kB in Atherosclerosis

University Of Pennsylvania, Philadelphia PA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Atherosclerosis is a slowly progressing chronic inflammatory disease of the medium and large arteries that is responsible for high mortality rates. Consequently, developing new effective strategies to prevent or cure atherosclerosis will profoundly impact human health care. Activation of vascular ECs (VECs) is crucial for the initiation and progression of atherosclerosis and our long-term research goal is to define the signals that control VEC activation, as this will reveal novel targets for new anti-inflammatory drugs. A central signaling mechanism in atherogenesis is activation of the NF-?B family of transcription factors. In the current model of NF-?B activation, signaling occurs via classical or non-canonical pathways, resulting in the activation of distinct NF-?B species that control discrete sets of pro-inflammatory genes. Genetic studies strongly implicate classical NF-?B in VECs in atherogenesis. However, as detrimental immunological side effects of small molecule IKKß inhibitors present a major roadblock to systemic clinical targeting of this crucial pathway, we propose to test the hypothesis that selective pharmacological inhibition of VEC-intrinsic classical NF-?B will prevent atherogenesis and/or reduce established atherosclerotic plaques. To test this hypothesis, we will utilize our recently developed innovative strategy to selectively deliver a classical pathway inhibitor to activated VECs in vivo and we will determine how this approach affects both the development and resolution of atherosclerosis in mice (Aim 1). While IKKß-driven classical NF-?B in VECs appears to play a key role in atherosclerosis, the function of IKK? is unexplored. Therefore, we generated mice specifically lacking IKK? in VECs (IKK?VEC) that we have crossed with ApoE-/- animals (IKK?VEC-E). Notably, our preliminary findings indicate that atherosclerosis is reduced in IKK?VEC-E mice. However, as we also found that IKK? controls both non-canonical NF-?B activation and a novel alternative pathway that unexpectedly activates classical NF-?B species, we will determine if either or both of these IKK?-driven pathways function in atherogenesis (Aim 2). Finally, while developing an in vivo model to assess epithelial cell-intrinsic IKK? function, we made the groundbreaking discovery that lymphatic function is compromised in mice that specifically lack IKK? in lymphatic epithelial cells (LECs) (IKK?LYVE1 mice). While lymphatic vessels appear normal in IKK?LYVE1 mice, lymph node (LN) development is compromised. As local lymphatic vessels are implicated in later stages of atherogenesis, we hypothesize that non-canonical NF-?B signaling in LECs will influence disease progression through its effects on lymphatic function and will test this hypothesis using our novel genetic model (Aim 3). Accomplishing our aims will provide new understanding of the roles of VEC- and LEC-intrinsic NF-?B in disease progression and the potential therapeutic value of selectively targeting classical or non-canonical NF-?B signaling in atherosclerosis patients.